Systems and methods for improved delivery of osteoinductive molecules in bone repair

Abstract

Systems and methods for preparing synthetic osteoinductive bone grafts are provided in which a porous ceramic granule, which may be incorporated within a biocompatible matrix material, is loaded with an osteoinductive agent. Loading of granules is facilitated in some cases by the use of low-pH buffers and pre-treatments.

What is claimed is: 
     
       1. A composition, comprising:
 a preformed calcium ceramic granule having a specific surface area greater than 30 m 2 /g and having an interconnected network of micropores defining at least one surface on an interior of the granule; and 
 an amount of osteoinductive protein adsorbed to the exterior surface of the granule and adsorbed onto the at least one interior surface, wherein the osteoinductive protein is distributed on a portion of the interior surface of the granule including on a portion of the interior surface within a radius of 20% of the average distance from the centroid of the granule to the outer surface of the granule, wherein a concentration of osteoinductive protein adsorbed to said portion of the interior surface within a radius of 20% of the average distance from the centroid to the outer surface of the granule is not less than 33% of a concentration of the osteoinductive protein adsorbed to the external surface of the granule. 
 
     
     
       2. The composition of  claim 1 , further comprising a biocompatible matrix, wherein ceramic granules are disposed within the biocompatible matrix. 
     
     
       3. The composition of  claim 2 , wherein the biocompatible matrix is a sponge having a plurality of pores, the pores having an average diameter of about 150 to about 300 microns. 
     
     
       4. A composition, comprising:
 a biocompatible porous polymer matrix; 
 a calcium ceramic granule contacting the porous polymer matrix, the calcium ceramic granule having a specific surface area greater than 30 m 2 /g and having an interconnected network of micropores defining at least one surface on an interior of the granule; and 
 an amount of an osteoinductive protein adsorbed onto the exterior surface and absorbed onto the at least one interior surface, wherein the osteoinductive protein is distributed on the interior surface including on a portion of the interior surface within a radius of 20% of the average distance from the centroid to the outer surface of the granule, wherein a concentration of osteoinductive protein adsorbed to said portion of the interior surface within a radius of 20% of the average distance from the centroid to the outer surface of the granule is not less than 33% of a concentration of the osteoinductive protein adsorbed to the external surface of the granule. 
 
     
     
       5. The composition of  claim 4 , wherein the ceramic granule is disposed within the biocompatible porous matrix. 
     
     
       6. The composition of  claim 5 , wherein the biocompatible porous matrix comprises collagen. 
     
     
       7. The composition of  claim 5 , wherein the biocompatible matrix is a sponge having a plurality of pores, the pores having an average diameter of about 150 to about 300 microns. 
     
     
       8. The composition of  claim 4 , wherein the osteoinductive protein is adsorbed to the at least one interior surface of the granule by a method including the step of contacting the granule with a first solution comprising the osteoinductive protein and a buffering agent having a pKa between 2.3 and 4.5, the solution having a pH less than 4.5. 
     
     
       9. A method of treating a patient, comprising the steps of:
 contacting a bony tissue of the patient with a composition, comprising:
 a calcium ceramic granule having a specific surface area greater than 30 m 2 /g and having an interconnected network of micropores defining at least one surface on an interior of the granule; and 
 an amount of osteoinductive protein adsorbed to an exterior surface of the granule and adsorbed onto the at least one interior surface, wherein the osteoinductive protein is distributed on a portion of the interior surface of the granule including on a portion of the interior surface within a radius of 20% of the average distance from the centroid to the outer surface of the granule, wherein a concentration of osteoinductive protein adsorbed to said portion of the interior surface within a radius of 20% of the average distance from the centroid to the outer surface of the granule is not less than 33% of a concentration of the osteoinductive protein adsorbed to the external surface of the granule. 
 
 
     
     
       10. The method of  claim 9 , wherein the bony tissue is selected from the group consisting of a site of a traumatic injury to the bone and a vertebra. 
     
     
       11. The method of  claim 9 , wherein the composition includes a biocompatible matrix, the ceramic granule disposed within the biocompatible matrix. 
     
     
       12. The method of  claim 11 , wherein the biocompatible matrix comprises collagen.